Project Summary-Abstract Preeclampsia (PE) remains a major health concern, affecting 5-10% of all pregnancies in the United States. It is a leading cause of maternal and perinatal morbidity and mortality. While the underlying mechanisms are not clear, it is believed that inadequate remodeling of the maternal vasculature leads to placental hypo-perfusion, resulting in chronic placental hypoxia/ischemia. In response the placenta releases pathogenic factors into the maternal blood stream, leading to widespread maternal endothelial dysfunction and hypertension. In recent years, a great deal of attention has focused on the role of altered immune function in the pathogenesis of PE. Chronic activation of immune mechanisms is associated with PE as preeclamptic women have an imbalance among CD4+ T lymphocytes (?TRegs ?TH17), increased cytolytic natural killer (NK) cells, and chronic systemic inflammation. These factors are thought to contribute to the pathophysiology of PE; however, the stimulus for the increased cytolytic NK cell number and function during PE has yet to be clearly defined. Furthermore, the significance of the cytolytic NK cells in the development of PE and hypertension has not been previously investigated. Natural killer cells make up 10% of lymphocytes in human peripheral blood and are identified by their expression of CD56 in the absence of CD3. NK cells function to provide front line defense against viral infections and malignantly transformed cells. NK cells can differentiate into two distinct subsets, type 1 (NK1) or type 2 (NK2). The NK1 subset is characterized by its release of IFN? and potent cytolytic activity upon activation whiel the NK2 subset is characterized by their release of the anti-inflammatory cytokines IL-5 and IL- 13 and a decrease in their cytolytic activity. Decidual natural killer cells make up 70-90% of the uterine leukocytes and are the most abundant maternal leukocyte population during the first trimester in human pregnancy. The main population of uterine NK (uNK) cells consists of the NK2 subset and these cells are thought to have multiple roles in human pregnancy. Preeclampsia is associated with a shift in the NK cell population from NK2 to NK1 (Type 1 shift); and previous investigators have suggested an important role for TH17s and IL-17, to activate the cytolytic function of NK cells in vitro. This proposal will explore the role of ?TH17s as regulators of cytolytic NK cells during placental ischemia. I will further explore the molecular mechanisms that regulate cytolytic NK cell activity. Finally, I propose to manipulation of the cytolytic NK cell population or manipulation of the factors that mediate cytolytic NK cell activation will attenuate the development of hypertension and intrauterine growth restriction, suggesting new therapeutic approaches for the management of preeclampsia. In order to test these hypotheses, a number of in vitro and in vivo approaches will be used.